Corrigendum: Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies.

[This corrects the article DOI: 10.3389/fnana.2021.664695.].

In the original article, there was a mistake in Table 1 as published.

Table 1

Summary of IUE-based rodent models of mTORopathies.

Gene	IUE age, cortical area	Migration defect/misplacement (M), Cytomegaly (C), Dendrite overgrowth (D)	Synaptic function and electrophysiological properties	Seizure phenotype	Other phenotypes	Pharmacological and/or genetic rescue	References
Pi3k iSH2-p110α (GOF)	E15.5	E18.5: M	–	–	–	–	Konno et al., 2005
Pi3k WT	E14.5	E18.5: M	–	–	–	–	Baek et al., 2015
*Pi3k E545K (GOF)	E14.5	E18.5: M, C	–	–	–	–	Baek et al., 2015
*Pi3k E545K (GOF)	E14-E15, SSC	–	P15-70 L2/3 PN: No change-RMP No change-RinputNo change-I/O (rheobase)No change-AP voltage threshold	–	–	–	Goz et al., 2020
*Pi3k E545K (GOF)	E14.5, SSC, CC	P24-28: C, DP60: M, C	P24-28, L2/3 PN: ↓ mIPSC frequency ↓ mIPSC amplitude	Spontaneous seizures	P60: ↓ GABAergic interneuron density	Rapamycin, 2 mg/kg every 48 h, P10-P30: rescued C, D, mIPSC frequency; partially rescued GABAergic interneuron density; no rescue of M, mIPSC amplitude	Zhong et al., 2021
Pten (CRISPR/Cas9 KO)	E14-E15 (rat)	P19: M, C, D	P21-P30, L2/3 PN: ↑ mEPSC frequency ↑ sEPSC frequencyNo change-RMP ↓ Rinput	–	–	–	Chen et al., 2015
Akt1 WT	E14.5	E16.5, E17.5, E18.5: enhanced migration	–	–	–	–	Itoh et al., 2016
Akt1 mΔPH (GOF)	E14.5	E16.5, E17.5: M	–	–	–	–	Itoh et al., 2016
Akt3 WT	E14.5	E18.5: M, CP20: M, C	–	~P28: Spontaneous bursts		Rapamycin, 3 mg/kg daily, E15.5-E18.5: rescued M, C	Baek et al., 2015
*Akt3 E17K (GOF)	E14.5	E18.5: M, CP20: M, C	–	~P28: Spontaneous seizures	No microglia reactivity	Rapamycin, 3 mg/kg daily, E15.5-E18.5: rescued M, CRapamycin, 3 mg/kg daily, P1-P3: no rescue of MReelin siRNA or Foxg1 T271A (LOF) expression: partially rescued M	Baek et al., 2015
Akt3 S472E (GOF)	E14.5	E18.5: M	–	–	–	–	Baek et al., 2015
Tsc1floxed/mutant,Cre IUE, 2-hit model	E15-16, SSC	P15: CP28: M, C	–	P15:↓ Seizure threshold	P15, P28: No astroglial reactivity	–	Feliciano et al., 2011
Tsc1(CRISPR/Cas9 KO)	E14	>P21: M, C	–	>P21: Spontaneous seizures	–	–	Lim et al., 2017
Tsc1(CRISPR/Cas9 KO)	E14-E15, SSC	–	P15-70 L2/3 PN: ↓ RMP (hyperpolarized) ↓ Rinput ↓ I/O (= ↑ rheobase) ↓ AP voltage threshold	–	–	–	Goz et al., 2020
Tsc2 (shRNA KD)	E14	E19: M, C	–	–	–	Rapamycin, 5 mg/kg daily, E15-E18: rescued M, C	Tsai et al., 2014
Tsc2 (shRNA KD)	E13.5, E16.5	E18.5, P2: M	–	–	–	Cul5 shRNA KD: rescued M	Moon et al., 2015
Tsc2(CRISPR/Cas9 KO)	E14	E18: M>P21: M, C	–	>P21: Spontaneous seizures	–	Rapamycin, 10 mg/kg daily, starting after seizure onset: rescued C; ↓ seizures	Lim et al., 2017
Rheb WT	E13.5, E14.5, E16.5	E18.5, P0, P2: M	–	–	–	Cul5 shRNA KD: rescued M	Moon et al., 2015
Rheb WT	E14.5, SSC	P0, P7: M	–	>P20:Spontaneous seizures	–	–	Reijnders et al., 2017
Rheb WT	E14.5-E16, mPFC, SSC	P14: M, C, D	–	–	–	–	Sokolov et al., 2018
Rheb WT	E14.5	–	–	No seizures	–	–	Zhao et al., 2019
Rheb S16H (GOF)	E15, mPFC	P8: M	–	–	P0: ↑ Axon growth	4EBP1 F113A (GOF) expression, S6K1/2 shRNA KD, or lithium chloride (GSK3 blocker), 10 mg/kg daily, E15-E19: rescued axon overgrowthGSK3βDN expression:rescued axon overgrowth; no rescue of M	Gong et al., 2015
Rheb S16H (GOF)	E15.5, mPFC	P0, P7, P28: MP24: CP28-P42: D	P28-P42 L2/3 PN: ↓ Spine density ↓ sEPSC frequency ↑ RMP (depolarized)	–	P7, P21-28: ↓ Autophagy	4EBP1 F113A (GOF) expression: rescued M, C; partially rescued D; restored RMP, sEPSC frequency; no rescue of spine densityS6K1/2 shRNA KD:no rescue of M	Lin et al., 2016
Rheb S16H, conditional(+ DCX-Cre; expression in migrating neurons)	E15.5, mPFC	P7: M	–	–	–	–	Lin et al., 2016
Rheb S16H (GOF)	E15.5, mPFC	P28: C, D>P56: M	–	>P56: Spontaneous seizures	>P56: ↑ Astroglial reactivity No change in GABAergic interneuron density	Rapamycin, 1 mg/kg every 48h, P1-P56: rescued M, C; ↓ seizures	Hsieh et al., 2016
Rheb S16H, conditional(+ tamoxifen-inducible Cre; postnatal expression)	E15.5, mPFC *P7 tamoxifen treatment	>P56: C, no M	–	>P56: Spontaneous seizures	–	–	Hsieh et al., 2016
Rheb S16H (GOF)	E15, mPFC	>P56: M, C	–	>P56: Spontaneous seizures	>P56: ↑ Microglial reactivity	–	Nguyen et al., 2019
Rheb S16H (GOF)	E15, SSC	P14: M, C, D	–	–	P14: ↑ Vascular density	Rapamycin, 0.5 mg/kg every 48 h, P1-P14: rescued D; partially rescued M, C; ↓ vascular density	Zhang et al., 2019
Rheb S16H (GOF)	E15, mPFC	>P28: M, C, D	–	>P42Spontaneous seizures	–	Flna shRNA KD: partially rescued M, C, D; ↓ seizuresPTI-125 (Flna modulator), 6 or 12 mg/kg 2x daily, P8-28: partially rescued C, DPTI-125 (Flna modulator), 12 mg/kg 2x daily, P8-65: ↓ seizures; no rescue of MPTI-125, 12 mg/kg 2x daily, P29-54: partially rescued C, D; ↓ seizures	Zhang et al., 2020
Rheb S16H (GOF)	E15.5, mPFC	>P84: M, C	P8-12, L2/3 PN: ↑ h current P26-42, L2/3 PN: ↑ RMP (depolarized) ↓ Rinput ↓ I/O (= ↑ rheobase) ↑ h current (and ectopic HCN4 expression) ↑ Sag response	>P84: Spontaneous seizures	–	Rapamycin, 1 mg/kg every 48h, P1-P56: ↓ HCN4 expressionKir2.1 expression:↓ RMP, ↓ I/O, ↓ seizures; no rescue of C, capacitanceHCN4NF expression:↓ RMP, ↓ h current, ↓ sag response, ↓ seizures; no rescue of C, I/O	Hsieh et al., 2020
**Rheb P37L (GOF)	E14.5, SSC	P0, P7: M	–	>P20:Spontaneous seizures	–	–	Reijnders et al., 2017
**Rheb P37L (GOF)	E14.5, SSC	P30: M, CP25: D	P21-25, L2/3 PN:No change-RMP ↑ Capacitance ↓ Rmembrane (= ↓ Rinput) ↓ I/O (= ↑ rheobase) No change-AP voltage threshold P21-25, contralateral, non-transfected L2/3 PN targeted by mutant axons: ↑ I/O, ↑ eEPSC amplitude in response to depolarizing mutant axons	>P21:Spontaneous seizures	P45: ↑ Axon growth	Rapamycin, 1 mg/kg daily, E15.5-E16.5: partially rescued M; no rescue of seizuresRapamycin, 10 mg/kg daily, starting after seizure onset for 7 days: ↓ seizuresRheb P37L deletion (before seizure onset at P14 or after seizure onset): ↓ seizures; no rescue of MTetanus toxin light chain expression (blocks axonal projection): prevented seizuresTetanus toxin light chain expression (before seizure onset at P14; blocks vesicular release): prevented seizures, I/O changes in contralateral neurons targeted by RhebTetanus toxin light chain expression (after seizure onset at P35; blocks vesicular release): ↓ seizures	Onori et al., 2020
Rheb P37L, conditional(+ tamoxifen-inducible Cre; postnatal expression)	E14.5, SSC *P7 or P21 tamoxifen treatment	No M	–	>P35:Spontaneous seizures	–	–	Onori et al., 2020
**Rheb S68P (GOF)	E14.5, SSC	P0, P7: M	–	>P20:Spontaneous seizures	–	–	Reijnders et al., 2017
*Rheb Y35L (GOF)	E14.5	E18.5: M, CP30: C	–	>P30:Spontaneousseizures	–	Rapamycin, 10 mg/kg daily, starting at P45 for 11 days: ↓ seizures	Zhao et al., 2019
mTOR WT	E14.5	P0: No M, C	–	–	–	–	Kassai et al., 2014
mTOR WT	E14	–	–	No seizures	–	–	Lim et al., 2015; Park et al., 2018; Kim et al., 2019
mTOR WT	E15 (rat)	E20: no M	–	–	–	–	Pelorosso et al., 2019
mTOR SL1+IT (GOF)	E14.5	P0: M, C	–	–	–	Rapamycin, 5 mg/kg, embryonic, or Raptor shRNA KD: rescued M, CS6K1/2 shRNA KD: rescued C	Kassai et al., 2014
mTOR SL1+IT (GOF)	E13.5, SSC	E17.5: M	–	–	–	–	Tarkowski et al., 2019
*mTOR L2427P (GOF)	E14	E18: M>P21: C	–	>P21: Spontaneous seizures	–	Rapamycin, 10 mg/kg daily, starting after seizure onset for 2 weeks: rescued C; ↓ seizures	Lim et al., 2015
*mTOR L2427P (GOF)	E14	–	–	–	>P56: Defective ciliogenesis ↓ Autophagy	Rapamycin, 10 mg/kg daily, starting after seizure onset for 2 weeks: rescued ciliogenesis	Park et al., 2018
*mTOR L2427P (GOF)	E14	E18, P7: MP21: C	P21, L2/3 PN: ↓ Spine density	>P21: Spontaneous seizures	E18: Translational dysregulation	Rapamycin, 5 mg/kg daily, E14-E17: rescued MeIF4E shRNA KD: rescued M, C, spine density; ↓ seizuresMetformin (eIF4E inhibitor), 200 mg/kg daily, P14-56: rescued C; ↓ seizuresMetformin, 200 mg/kg daily, P84-114: ↓ seizuresADK shRNA KD or 5-ITU (ADK inhibitor), 1 or 2.6 mg/kg, 2x daily for 10 days: ↓ seizures	Kim et al., 2019
*mTOR A1459D (GOF)	E14.5	E18.5: M, C	–	–	–	–	Hanai et al., 2017
*mTOR C1483Y (GOF)	E14	E16, E18: M>P56: C	–	>P21: Spontaneous seizures	>P56: Defective ciliogenesis ↓ Autophagy	Rapamycin, 10 mg/kg daily,after seizure onset for 2 weeks: rescued C, ciliogenesis defectsOfd1 shRNA KD: rescued M, ciliogenesis defects; no rescue of C, seizuresWnt5a expression: rescued M	Park et al., 2018
*mTOR C1483Y (GOF)	E14	E18, P7: MP21: C	P21, L2/3 PN: ↓ Spine density	>P21: Spontaneous seizures	E18: Translational dysregulation	Rapamycin, 5 mg/kg daily, E14-E17: rescued MeIF4E shRNA KD: rescued M, C, spine density; ↓ seizuresMetformin (eIF4E inhibitor), 200 mg/kg daily, P14-56: rescued C; ↓ seizuresMetformin, 200 mg/kg daily, P84-114: ↓ seizuresADK shRNA KD or 5-ITU (ADK inhibitor), 1 or 2.6 mg/kg, 2x daily for 10 days: ↓ seizures	Kim et al., 2019
*mTOR C1483Y (GOF)	E13.5, SSC	E17.5: M, C	–	–	–	–	Tarkowski et al., 2019
*mTOR L1460P (GOF)	E13.5, SSC	E17.5: M, C	–	–	–	–	Tarkowski et al., 2019
*mTOR S2215Y (GOF)	E13.5, SSC	E17.5: M, C	–	–	–	–	Tarkowski et al., 2019
mTOR R2505P (GOF)	E13.5, SSC	E17.5: M, C	–	–	–	–	Tarkowski et al., 2019
mTOR L2427T (GOF)	E13.5, SSC	E17.5: M	–	–	–	–	Tarkowski et al., 2019
*mTOR S2215F (GOF)	E15 (rat)	E20: MP28: C	–	–	–	–	Pelorosso et al., 2019
Stradα (shRNA KD)	E14	E17, E19: M	–	–	–	–	Orlova et al., 2010
Stradα (shRNA KD)	E14	E19: M	–	–	–	Rapamycin, 5mg/kg daily, E15-E19: rescued M	Parker et al., 2013
Depdc5(CRISPR/Cas9 KO)	E14.5	E18.5: MP21-P63: M, CP20-P24: D	P20-P24, L2/3 PN:No change-Spine density ↑ Spine head width No change-sEPSC frequency ↑ sEPSC amplitude ↑ Capacitance ↓ Rinput ↓ I/O (= ↑ rheobase)	>P21: Spontaneous seizures	–	Rapamycin, 1 mg/kg single injection at E15: rescued M	Ribierre et al., 2018
Depdc5(CRISPR/Cas9 KO)	E13-E14 (rat)	P21-30: C	P21-28, L2/3 PN: No change-RMP ↓ Rinput Doublet AP firing	>P60: Spontaneous seizures	–	Everolimus, P10-21: rescued C	Hu et al., 2018
Depdc5floxed/mutant,Cre IUE, 2-hit model	E14.5	P15: CP42: M, C, D	–	P42:↓ Seizure threshold	–	Depdc5 WT or Depdc5 Q542P (GOF) expression: rescued CDepdc5 F164 del (LOF) expression: no rescue of C	Dawson et al., 2020
Nprl3(CRISPR/Cas9 KO)	E14	P3: M, C>P35: C	–	>P35:↑ Cortical excitability↓ Seizure threshold	–	Rapamycin, 1 mg/kg single injection at E15: rescued M, C	Iffland et al., 2020

The table is organized by position of genes in the PI3K-mTOR pathway and GATOR1 complex, variant, and date of publication. All gene variants activate mTORC1 signaling. Stars in front of gene name denote human de novo somatic (.

Three rows of cited work (Rheb S16H, Hsieh et al., 2020; Rheb P37L, Reijnders et al., 2017, and Rheb P37L, Onori et al., 2020) were omitted.

Additionally, one of the cited studies (Rheb S16H) had the incorrect reference Zhang et al., 2019. Zhang, L., Huang, T., Teaw, S., and Bordey, A. (2019). Hypervascularization in mTOR-dependent focal and global cortical malformations displays differential rapamycin sensitivity. Epilepsia 60, 1255–1265. doi: 10.1111/epi.15969. Instead, it should be Zhang et al., 2020. Zhang, L., Huang, T., Teaw, S., Nguyen, L. H., Hsieh, L. S., Gong, X., et al. (2020). Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations. Sci. Transl. Med. 12:eaay0289. doi: 10.1126/scitranslmed.aay0289.

The corrected Table 1 appears below.

The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.